The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Stem cell therapy has become an active area of research in cardiology following the demonstration that these cells play a role in neovascularization and possibly in improvement of cardiac function following myocardial infarction. Stem cells also have shown promise in preclinical and clinical studies for the treatment of ischemic syndromes such as coronary artery disease, congestive heart failure, and peripheral artery disease. See Perin, et. al., Circulation 2003 107:r75-r83; Haider, et al., J. Mol. Cell. Cardiol. 2005 38(2):225; Deschaseaux, et. al., Cardiovascular Res. 2005 65(2):305; Thompson, et. al., J. Heart Lung Transplant. 2005 24(2):2051; US Patent Application publication No. 20060008450. Methods for efficient expansion of stem cells in culture have been described. See Feugier et al., J. Hematotherapy and Stem Cell Res. 2002 11:127-138.
Several mechanisms of action have been postulated for stem cell derived therapeutic effects in these disease models; 1) Endothelial precursors present in preparations of bone marrow stem cells induce neovascularization in ischemic tissue and that this neovascularization enhances blood flow which prevents apoptosis of damaged cells and promotes tissue repair. See Itescu, J. Mol. Med. 2003 81 (5):288; Orlic, Proc. Natl. Acad. Sci. (USA) 2001 98:10344; 2) Bone marrow derived stem cells induce endogenous cardiomyocytogenesis. See Yoon, et. al. J. Clin. Invest. 2005 115:326; 3) Mammalian cells have been shown to be capable of building nanotubular “highways” between stem cells and cardiomyocytes, and cytoplasmic organelles and fluids are transported into the cardiomyocytes. See Koyanagi, et al., Circulation Res. 200596:1039-1041; and 4) Paracrine (humoral) factors secreted by bone marrow derived cells promote cardiomyocyte survival. See Gnecchi, et al., Nat. Med. 2005 11:367-368.
Direct injection of CD34+ bone marrow stem cells or autologous myoblasts has been found to improve clinical outcome in ischemic diseases such as post myocardial infarction. However, ex-vivo processing of cells poses significant technical challenges such as lack of adequate modes of high efficiency delivery. See Takagi, et al. J. Biosci Bioengineer. 2005 99:189-196. In addition, there is a complicated regulatory network for the manufacturing of cell products involving maintenance of adequate sterility, cold chain transport, quality control testing logistics, etc. (Bosse, et al., Ann Hematol 2005 79:469-476. Finally, injection of non-cardiac cells into the heart may cause arrhythmia which can be life threatening. See Menasche, et al., J. Am. Coll. Cardiol. 2003 41(7):1078-1083.
The administration of particular cytokines such as SCF and G-CSF have been shown to enhance recovery of heart function following acute myocardial infarction. See Orlic et al., Proc. Natl. Acad. Sci (USA) 2001 98(18):10344-10349; Takano et al., Current Pharmaceutical Design 2003 9:1121-1127; Ohtsuka et al., The FASEB J. 2004 18(7):851-3. Administration of adenoviral vectors encoding VEGF165, VEGF189, ANG-1 or SDF-1, has been used to increase plasma levels of hematopoietic stem cells and endothelial progenitors. Rafii et al., Gene Therapy 2002 9:631-641.
Stem cell factor (“SCF”) is a ligand for the tyrosine kinase receptor known as c-kit. See Zsebo, Cell 1990, 63 (1) 213-24); U.S. Pat. No. 6,218,148. SCF induces the proliferation of primitive CD34+ bone marrow progenitors. It has been shown in a number of studies in mice, dogs, and humans, that the SCF/c-kit pathway is involved in the normal process of repair following ischemic damage. Mice genetically deficient in c-kit signaling, has shown that recovery after myocardial infarction depends on SCF induced proliferation of c-kit+ cells in the heart. See Fazel, et. al. “Stem cell factor receptor and cardiac regeneration after myocardial infarction” Am. Heart Assoc. Scientific Sessions 2004, Circulation 2004 Oct. 26; 110(17 Suppl) abstract no. 2182; Ayach, et al., “c-Kit+ BM cells are essential for reducing deteriorating myocardial and heart function post-myocardial infarction” Am. Heart Assoc. Scientific Sessions 2004, Circulation 2004 Oct. 26; 110(17 Suppl) abstract no. 317. SCF is induced in canine cardiac tissue after myocardial infarction. See Frangogiannis, et al., Circulation 1998 98:687. SCF mRNA is induced within 72 hours of reperfusion following myocardial infarction See Frangogiannis et al 1998. SCF production from infracted myocardium has been traced to a subset of macrophages resident therein, and increased density of c-kit+ mast cells at the ischemic site. Mast cells can secrete angiogenic factors such as vascular endothelial growth factor (VEGF), which promote the revascularization process. See Heissig, et al., J. Exp. Med. 2005 202(6):739-50. SCF expression was found to be decreased in the heart following myocardial infarction. See Woldbaek, et. al., Acta Physiol Scand 2002 175:173-181. In vitro studies showed that SCF gene expression can be suppressed by proinflammatory cytokines including TNF-A. See Andrews, et al., 1992 Blood 80:365 A; Langley, Blood, 1993 81:656-660.
U.S. Pat. No. 6,723,561 describes retroviral vectors encoding SCF and retroviral packaging cell lines expressing SCF and use of same to deliver a foreign nucleic acid to stem cells in a subject.